The present invention relates to substituted benzamides, which are enhancers of transcription factor AP (activator protein)-1, to compositions containing them, and to methods for clinical treatment of diseases associated with immune suppressive states and to the use of the benzamides for the preparation of a medicament for stimulation of transcription factor AP-1. Such compounds are particularly useful in the treatment of a variety of diseases associated with immune suppression and low capability to produce IL (interleukin)-2. Such diseases include cancer, autoimmune disease and infectious disease. More particularly, the present invention relates to benzamide derivatives suitable for the treatment of, for example, solid tumours, rheumatoid arthritis (RA) and AIDS. The compounds of the present invention are also suitable for the treatment of manic-depressive illness.
AP-1 is a transcriptionally active protein heterodimer containing members of the Fos (e.g. c-Fos, FosB, Fra-1, Fra-2) and the Jun (e.g. c-Jun, JunB, JunD) family of proteins. The AP-1 transcription factors are stimulated by e.g. growth factors, cytokines, T cell activators and neurotransmitters and act as dimers binding to DNA in many promoters including proteases and cytokines like IL-2. C-Jun and c-Fos knock-out mice have been produced showing embryonic lethality and osteopetrosis/lymphopenia/behavioural abnormalities, respectively (Johnson et al., 1992). These results emphasise that the AP-1 site is pivotal in many different genes and points out lymphocyte regulation and behaviour, regulation in the central nervous system, as two distinct biological hotspots. Therefore, immune suppression with low capability to produce IL-2 and behavioural disorders are two very different medical indication areas where AP-1 activity is suboptimal and where AP-1 enhancers can be applied.
In U.S. Pat. No. 3,177,252 some substituted benzamide derivatives including metoclopramide (The Merck Index 12th Ed., entry 6226) are disclosed as being useful for the treatment of emesis.
The compound metoclopramide may be associated with depression and, because of its central as well as peripheral dopamine-blocking properties, may cause most unwanted tardive dyskinesia. Structure-activity relationship studies have demonstrated the link between the diaminoethylene bridge and the dopamine-D2 blockade.
In GB 1,174,956 quaternary ammonium salts of N-substituted benzamide derivatives and their action to accelerate the automatic motility of digestive tract are disclosed.
In J. Org. Chem. USSR 22, 578-582 (1986), the synthesis of N-(3-dimethylamino-propyl)-3-nitro-4-acetylaminobenzamide is described.
In U.S. Pat. No. 4,568,685 some N-[(1H-1,2,4-triazol-1-yl)alkyl]arylamides are disclosed as being inhibitors of thromboxane synthetase enzyme.
In U.S. Pat. No. 4,568,687 some N-[xcfx89(1H-imidazole-1-y1)alkyl]arylamides are disclosed as being inhibitors of thromboxane synthetase enzyme and are also useful in the treatment of hypertension and myocardial ischemia.
In Analytical Profiles of Drug Substances vol. 4, K Florey, Ed. (Academic Press, New York, 1975) pp 333-383, procainamide (The Merck Index 12th Ed., entry 7936) is described as an antiarrhytmic agent.
We have now discovered a novel method of stimulating the transcription factor AP-1 using substituted benzamides.
Immune Suppression in Cancer, Autoimmune Disease and Infectious Disease
Immune system-based approaches for the treatment of malignant disease have focused on cytolytic effector cells such as cytotoxic T lymphocytes (CTL), and natural killer (NK) cells. It has also been demonstrated that tumour-bearing mice can be cured using a wide variety of approaches, some of which involve IL-2 mediated enhancement of CTL and NK cell activity. However, the apparent success in mice stands in contrast to the current situation in the clinic, wherein only a minority of patients have thus far benefited from CTL- or NK cell-based anti-tumour approaches. This is probably a result from tumour-induced immune suppression (Whiteside, 1999; Kiessling et al., 1999). One of the underlying causes of tumour-associated immune suppression of CTL and NK cell activity, the intracellular signalling deficiency resulting from reduction of the TCR/CD3 zeta chain expression of the T cells, is also shared with HIV infection, leprosy, and rheumatoid arthritis. This signalling deficiency is overrun by IL-2 treatment in vitro. IL-2 is a central cytokine in the development of functional immune responses and it has been clearly shown that the AP-1 site of the IL-2 promoter is pivotal for optimal activity (Sundstedt and Dohlsten, 1998). Distinct benzamides would therefore represent an alternative treatment for immune stimulation and IL-2 enhancement in immune suppressive states of disease. In addition, several treatment regiments such as cytostatic and radiation therapy applied in the treatment of cancer result in unwanted immune suppression, an induced state that would be compensated for by administering compounds of the present invention.
Manic-Depressive Illness
Lithium and sodium valproate (VPA) (The Merck Index 12th Ed., entry 10049) are effective in the treatment of bipolar disorders (manic-depressive illness) and may function through the regulation of signal transduction pathways and transcription factors such as c-Fos and c-Jun, which in turn results to changes in gene expression. The long-term efficacy of lithium and VPA in bipolar disorders suggests that the regulation of gene expression may be an important target for these drugs. These two structurally highly dissimilar agents, lithium and VPA, increase AP-1 DNA binding activity in areas of rodent brain ex vivo and in human neuronal cells in culture (Yuan et al., 1998; Chen et al., 1999). Both treatments also increase the expression of a reporter gene driven by an AP-1-containing promoter, and mutations in the AP-1 sites of the reporter gene promoter markedly attenuate these effects. Both treatments also increase the expression of several endogenous proteins, which genes are known to be regulated by AP-1. These effects suggest that the temporal regulation of AP-1 mediated gene expression in critical neuronal circuits may play a role in the long-term therapeutic efficacy of lithium and VPA and point out that also other AP-1 enhancers like distinct benzamides could potentially act as modulators of e.g. manic-depressive illness.